For about 300,000 people in the USA with Juvenile Myoclonic Epilepsy (JME) and about 5 to 10 million persons, worldwide, with this disease, there is no cure. Thus, our general purpose is to accelerate discovery of epilepsy causing genes for JME, their pathogenetic mechanisms and cures through an international GENESS consortium. This consortium includes various sites in the developing world which provide human genetic resources, such as many large families, that far surpass what can be accomplished in Western societies like the USA. To the present time, most common genetic epilepsies are thought to be due to ion- channelopathies. Here we hypothesize that common epilepsies, such as JME, are caused by mutations in developmental genes that are involved in neurogenesis, apoptosis and neuroblast migration, such as genes with EF hand calcium binding motif like Myoclonin1/EFHC1. To test the hypothesis of developmental genes causing JME in preliminary studies, we used traditional linkage analysis and genome-wide scanning, then fine mapping in five large JME families (003, 0J1, 040, 106 and 017) and defined five new putative chromosome loci whose candidate genes are mainly developmental genes. Families (0J1, 106 and 016) which reached LOD score of 3.3 are highest priority and will be studied first in Aim 1 as we search for mutations that segregate with affecteds in 3 or 4 generations families using LightScanner system and sequencing. Examples of candidate developmental genes we will study are EGLN3, an apoptosis gene in Family 106, CREG2, an enhancer of stem cells, in Family 017, Centrin1 with 4 EF-hands in Family 003,GPRIN2, an inducer of neurite outgrowth, in Family 040 and Swiprosin (EFHD2 with 2 EF hands) in probands of 28 CAE/JME families. Aim 2 (Yrs2-3) will replicate linkage using the same STRPs/SNPs markers linked to chromosomes 6p12-q14, 14q11.2, 2q11.2, 18p11.23 and 10q11.2-21 to screen 14 other large 'DNA ready' JME families. We will then use constructed STS and tSNP haplotypes to screen 239 other medium-size 'DNA ready' families with JME and look for more recombinations. Aim 3 (Yrs3-4)will genome scan 681 samples of 80 large and medium-sized 'DNA-ready' JME families with Illumina Human Linkage set (6095 SNPs) already approved by CIDR (NIH National Human Genome Research Institute) and look for more epilepsy causing developmental genes. Aim 4 (Yrs 1-5) will collect DNA from 387 more multiplex/multigenerational and simplex families, and combine them with the already-collected 614 JME families and 1000 controls. We will apply to CIDR (NIH National Human Genome Research Institute) to genome scan all 1000 JME families/singletons and 1000 controls using the Illumina Human 1 M Bead chip (includes 1 M SNPs and 56K CNV probes) for joint analysis of linkage and linkage disequilibrium in Year 5. Only by defining (1) high-risk major JME genes and developing their knockout/knockin mice models, and (2) JME risk alleles that contribute to their complex genetics can pathogenetic mechanisms be unraveled and hopes for cures become a reality. PUBLIC HEALTH RELEVANCE: For about 300,000 people in the USA with Juvenile Myoclonic Epilepsy (JME) and about 5 to 10 million persons, worldwide, with this disease, there is no cure. To find a cure, we will define developmental Mendelian JME genes involved in neuronal genesis, migration and death, such as myoclonin with one EF hand calcium binding motif and the non-Mendelian risk alleles that contribute to complex genetics. Cures in JME can become a reality only by defining its many genes and then unravelling their epilepsy/disease causing mechanisms.